Proof-of-Concept Study of Monitoring Cancer Drug Therapywith Cerenkov Luminescence Imaging

Yingding Xu*, Edwin Chang*, Hongguang Liu, Han Jiang, Sanjiv Sam Gambhir, and Zhen Cheng

Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Canary Center at Stanfordfor Cancer Early Detection, Stanford University, Stanford, California

Cerenkov luminescence imaging (CLI) has emerged as a lessexpensive, easier-to-use, and higher-throughput alternative toother nuclear imaging modalities such as PET. It is expectedthat CLI will find many applications in biomedical research suchas cancer detection, probe development, drug screening, andtherapy monitoring. In this study, we explored the possibility ofusing CLI to monitor drug efficacy by comparisons against PET.To assess the performance of both modalities in therapy mon-itoring, 2 murine tumor models (large cell lung cancer cell lineH460 and prostate cancer cell line PC3) were given bevacizumabversus vehicle treatments. Two common radiotracers, 39-deoxy-39-18F-fluorothymidine (18F-FLT) and 18F-FDG,were used tomon-itor bevacizumab treatment efficacy. Methods: One group ofmice (n 5 6) was implanted with H460 xenografts bilaterally inthe shoulder region, divided into treatment and control groups(n 5 3 each), injected with 18F-FLT, and imaged with PET imme-diately followed by CLI. The other group of mice (n 5 6) wasimplanted with PC3 xenografts in the same locations, dividedinto treatment and control groups (n 5 3 each), injected with18F-FDG, and imaged by the same modalities. Bevacizumabtreatment was performed by 2 injections of 20 mg/kg at days0 and 2. Results: On 18F-FLT scans, both CLI and PET revealedsignificantly decreased signals from H460 xenografts in treatedmice from pretreatment to day 3. Moderately increased to un-changed signals were observed in untreated mice. On 18F-FDGscans, both CLI and PET showed relatively unchanged signalsfrom PC3 tumors in both treated and control groups. Quantifica-tions of tumor signals of Cerenkov luminescence and PET imagesshowed that the 2 modalities had excellent correlations (R2 .0.88 across all study groups). Conclusion: CLI and PET exhibitexcellent correlations across different tumor xenografts and radio-tracers. This is the first study, to our knowledge, demonstratingthe use of CLI for monitoring cancer treatment. The findings war-rant further exploration and optimization of CLI as an alternative toPET in preclinical therapeutic monitoring and drug screening.

Key Words: therapy monitoring; Cerenkov luminescenceimaging; radionuclides; optical imaging; PET; Avastin

J Nucl Med 2012; 53:312–317DOI: 10.2967/jnumed.111.094623

The emerging field of molecular imaging has yieldedpromising applications in both preclinical and clinical re-search in recent years (1). It has witnessed important ad-vances in medical diagnosis of diseases including cancer,cardiovascular diseases, and neurologic diseases; noveltreatment modalities; and therapy monitoring. A wide vari-ety of modalities in molecular imaging are now available toresearchers and physicians alike. These include PET, opti-cal imaging (OI), MRI, SPECT, and ultrasound. Amongthese options, the nuclear imaging modality PET is notablefor its high sensitivity and excellent quantification potentialyet suffers from poor spatial resolution, high cost, and lowavailability to basic researchers. On the other hand, OIfeatures high sensitivity, short scanning time, and highthroughput. However, OI is limited mostly to preclinicalapplications because of limited penetration and significantscattering of optical signals in vivo.

In recent years, potential applications of Cerenkovradiation (CR) in molecular imaging have gained credencebecause several groups of researchers have independentlyshowed that luminescence resulting from CR can be used toimage radionuclides, an application that once was solely inthe domain of nuclear imaging modalities such as PET andSPECT (2–8). Originally discovered in 1934 by Russianphysicist Pavel Alekseyevich Cerenkov and his colleagues,CR is a form of electromagnetic radiation emitted whena charged particle such as a positron or an electron travelsat a speed beyond the speed of light in a dielectric medium(9,10). The charged particle disrupts the electromagneticfield of the medium, temporarily displaces the electronsin the atoms of the medium, and subsequently causes theemission of photons when displaced electrons return to theground state. For example, the initial speed of an 18F pos-itron with the maximum relativistic kinetic energy of 635keV can be calculated to be 0.90c (c represents the speed oflight in a vacuum), which is significantly higher than thespeed of light in water (0.75c). As the charged positrontravels in water, it gradually loses its kinetic energy andspeed, but as long as its speed remains superluminal, CRwill be continuously emitted in the form of photons. IlyaFrank and Igor Tamm, colleagues of Cerenkov, were thefirst to calculate the number of photons produced by CR,

Received Jun. 20, 2011; revision accepted Sep. 7, 2011.For correspondence contact: Zhen Cheng, Molecular Imaging Program at

Stanford, Department of Radiology, Bio-X Program, Canary Center atStanford for Cancer Early Detection, 1201 Welch Rd., Lucas Expansion,P095, Stanford University, Stanford, CA 94305.E-mail: zcheng@stanford.edu*Contributed equally to this work.Published online Jan. 12, 2012.COPYRIGHT ª 2012 by the Society of Nuclear Medicine, Inc.

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and Ross later derived a table of numerically integratedsolutions that was based on their formula (11). It was esti-mated that one 18F decay would produce an average of 3photons in water using this table (3).Several groups have demonstrated that Cerenkov lumines-

cence imaging (CLI) can be used for in vivo tumor imaging,imaging probe development, and reporter gene imagingamong other applications (2,3,5,12,13). One of the reasonswhy CLI has enjoyed some success in molecular imaging isthat it takes advantage of luminescence signals generatedfrom radioactive probes, a good number of which have al-ready been approved for clinical uses in nuclear medicineand have found many important applications in both preclin-ical and clinical research. Combined with the significantlyreduced cost and greater availability of detectors when com-pared with nuclear imaging modalities such as PET, CLI isbeing considered as a new and alternative molecular imagingmodality.One important application of CLI that has not been

explored thus far is cancer drug therapy monitoring. Suchmonitoring would be essential for preclinical drug de-velopment and screening and potentially significant forclinical uses as well. PET and SPECT have long beenapproved and used for cancer diagnosis and therapymonitoring. These modalities have also been widely usedfor preclinical research, drug screening, and other relatedfields. In theory, CLI visualizes the same radionuclides asPET and SPECT, albeit with a quite different mechanism;thus, a good correlation could exist between the 2techniques. If a good correlation does exist in cancertherapy monitoring, then CLI could become an attractivealternative to the nuclear imaging modalities. Our grouppreviously showed that an excellent correlation betweenCLI and PET did exist in 18F-FDG imaging of C6-FLucsubcutaneous tumors (2). Thus, we hypothesized that thiscorrelation persists in long-term imaging of mouse xeno-grafts being treated by anticancer agents. Accordingly, thisreport represents a proof-of-concept study to show thecapabilities of CLI for cancer therapy monitoring. We se-lected bevacizumab (Avastin; Genentech/Roche) as ourdrug of choice because it is a well-known angiogenesisinhibitor that has been approved for the treatment of variouscancers, including lung, colorectal, and kidney (14–17).

MATERIALS AND METHODS

GeneralAll chemicals obtained commercially were of analytic grade and

used without further purification. 18F-FDG and 39-deoxy-39-18F-fluo-rothymidine (18F-FLT) were produced by the Radiochemistry Fa-cility at Stanford University. The human large cell lung cancer cellline H460 and prostate cancer cell line PC3 were obtained fromAmerican Type Culture Collection. Female athymic nude mice (nu/nu), obtained from Charles River Laboratories, Inc., were 4–6 wkold. All instruments, including reversed-phase high-performanceliquid chromatography, PET dose calibrator, and tumor cell lines,are the same as described in our previous publication (18).

Tumor ModelsAll animal studies were performed in compliance with federal

and local institutional rules for the conduct of animal experimen-tation. H460 cells were cultured in RPMI 1640 medium supple-mented with 10% fetal bovine serum and 1% penicillin/streptomycin (Invitrogen Life Technologies). PC3 cells werecultured in F-12K (Kaighan) medium with 2 mM L-glutamine sup-plemented with 10% fetal bovine serum and 1% penicillin-strepto-mycin. Both cell lines were maintained in a humidified atmosphereof 5% CO2 at 37�C, with the medium changed every other day. A75% confluent monolayer was detached with trypsin and dissociatedinto a single-cell suspension for further cell culture. Approximately1 · 106 H460 or PC3 cells suspended in phosphate-buffered saline(Invitrogen) were implanted subcutaneously in both left and rightshoulders of nude mice. Tumors were allowed to grow to 150–200mm3 (2–4 wk; 2 wk for H460, 4 wk for PC3, measured by standardcaliper measurement), and the tumor-bearing mice were subjectedto in vivo imaging via PET and CLI.

PETSmall-animal PET of tumor-bearing mice was performed on an

R4 rodent model scanner (Siemens Medical Solutions USA, Inc.).The mice were anesthetized with 2% isoflurane (Aerrane; Baxter)and placed prone and near the center of the field of view of thesmall-animal PET scanner. Three-minute static scans were ob-tained, and the images were reconstructed by a 2-dimensionalordered-subsets expectation maximum algorithm. No backgroundcorrection was performed. The method for quantification analysisof the images was the same as reported previously (18). The PETstudies were performed according to the same schedule as those ofCLI studies, with CLI performed immediately after the corre-sponding PET (Fig. 1).

CLICLI was performed with an IVIS Spectrum system (Caliper

Life Science). For all in vivo studies, radionuclides were diluted inphosphate-buffered saline. Wavelength-resolved spectral imagingwas performed using an 18-set narrow-band emission filter (490–850 nm). Animals were placed in a light-tight chamber underisoflurane anesthesia. Each acquisition, with or without filters,took 1–5 min for all studies. Images were acquired and analyzedusing Living Image 3.0 software (Caliper Life Sciences). Thedorsal skin area was used to calculate the signal intensity of back-ground tissue. The optical signal was normalized to photons persecond per square centimeter per steradian (p/s/cm2/sr). One groupof mice (n 5 6) was implanted with H460 xenografts bilaterally inthe shoulder region, divided into treatment and control groups (n 53 each), injected with 18F-FLT (7.3–8.0 MBq [198–215 mCi]) viathe tail vein, and imaged with PET immediately followed by CLI.Imaging studies were always done at days21, 1, and 3 with respectto day 0, defined by the first dose of bevacizumab (Fig. 1A). An-other group of mice (n 5 6) was implanted with PC3 xenografts inthe same locations, divided into treatment and control groups (n5 3each), injected with 18F-FDG (6.4–7.5 MBq [174–202 mCi]) via thetail vein, and imaged by the same modalities. Bevacizumab treat-ment was performed by 2 injections of 20 mg/kg at days 0 and 2.For the 18F-FDG imaging study, the mice were kept fasting over-night before the experiment.

Statistical MethodsQuantitative data were expressed as mean 6 SD. Means were

compared using the Student t test. A 95% confidence level was

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chosen to determine the significance between groups, with P val-ues of less than 0.05 indicating significant differences.

RESULTS

Tumor Growth Kinetics

The 2 tumor models, H460 and PC3, exhibited differenttumor growth kinetics (Fig. 2). Measurements of the 3dimensions of the H460 xenografts were done at days25, 23, 21, 1, 2, 3, 4, and 5 with respect to day 0, theday of the first injection of bevacizumab. The growth ki-netics plots showed that bevacizumab-treated xenograftshad significantly retarded growth rates (P , 0.01, n 5 6)when compared with the vehicle-administered controls(Fig. 2A). Measurements of the PC3 xenografts were per-

formed at days 28,24,22, 0, 1, 2, 3, 4, and 5 with respectto day 0, and the growth kinetics plot also showed a signif-icantly impeded (P , 0.01, n 5 6) growth in the treatmentgroup. Interestingly, the effect was more subtle than in theH460 counterpart (Fig. 2B).

Cancer Therapy Monitoring with CLI and PET

In vivo cancer therapy monitoring via CLI and PET wasdemonstrated using 2 well-known PET probes, 18F-FLT and18F-FDG (Fig. 3). 18F-FLT has been widely used for im-aging of tumor proliferation (19–21). On the other hand,18F-FDG has been mostly used for imaging of tumor me-tabolism (22–24). H460 tumor–bearing mice were dividedinto treatment and control groups (n 5 3 each), injected

FIGURE 1. Schematic of experimental de-

sign. Tumors were implanted bilaterally inshoulder region and allowed to grow to

150–200 mm3, and tumor-bearing mice

were subjected to in vivo imaging via PETand CLI at day 21, 1, and 3. Bevacizumab

treatment was performed by 2 injections of

20 mg/kg at days 0 and 2. For 18F-FDG im-

aging study, mice were kept fasting over-night before experiment.

FIGURE 2. (A) Tumor growth kinetics for H460 xenografts. Measurements were made at days 25, 23, 21, 1, 2, 3, 4, and 5. (B) Tumor

growth kinetics for PC3 xenografts. Measurements were made at days28,24,22, 0, 1, 2, 3, 4, and 5. For both figures, day 0 indicates firstdose of bevacizumab.

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with 18F-FLT (7.3–8.0 MBq [198–215 mCi]) via the tailvein, and imaged with PET immediately followed byCLI. Bevacizumab treatment was performed by 2 injectionsof 20 mg/kg at days 0 and 2 for the treatment group. For18F-FLT scans, as observed by visual inspection, a goodcorrelation in signal exists between CLI and PET. The datarevealed significantly decreased signals from H460 xeno-grafts in treated mice up to day 3 after treatment (Fig. 3, topleft). Moderately increased to unchanged signals were ob-served in vehicle-treated mice during the same period (Fig.3, top right). PC3 tumor–bearing mice were also dividedinto treatment and vehicle control groups (n 5 3 each),injected with 18F-FDG (6.4–7.5 MBq [174–202 mCi]) viathe tail vein, and imaged by the same modalities. Slightlydifferent from 18F-FLT scans of H460 xenografts, 18F-FDGscans of PC3 xenografts via both modalities showed rela-tively unchanged signals in both drug-treated and vehicle-administered groups (Fig. 3, bottom left and bottom right,respectively). However, good correlations according to vi-sual inspection were observed in this group of scans. Ofnote, the heart, which has high signal intensity on PETscans because of its high metabolic rate, is barely visiblewhen scanned by the IVIS Spectrum because of its deeplocation inside the murine body.

Quantitative analysis of both Cerenkov luminescenceimages and PET images was performed, and correlationanalysis was also performed by fitting with linear re-gression (Fig. 4). R2 values were 0.9309, 0.9488, 0.9294,and 0.8880 for the H460 treatment group, H460 controlgroup, PC3 treatment group, and PC3 control group, re-spectively (Fig. 4A, 4B, 4C, and 4D, respectively). Notably,the slopes of the fits are also numerically close (1575, 1587,1584, and 1552 for the H460 treatment group, H460 controlgroup, PC3 treatment group, and PC3 control group, re-spectively), suggesting an excellent fit via linear regression,even if data of all 4 groups are conglomerated.

DISCUSSION

CLI is an emergent molecular imaging technique that hasmany possibilities in both biomedical research and clinicalapplications (2,3,7,25,26). The principle of this imagingmethodology is to take advantage of the intrinsic CR fromcertain radionuclides (including, but not limited to, both b1

and b2-emitters) to image radioactive molecular probesthat are traditionally captured by PET or SPECT and useOI techniques to harvest imaging signals. CLI technologyhas several distinctive advantages: it is inexpensive (com-pared with nuclear imaging techniques), it is easier to use, it

FIGURE 3. Comparison between Ceren-

kov luminescence and PET images. White

arrows point to tumors in all panels. (Top

left) 18F-FLT scans of representative H460tumor–bearing mouse during bevacizumab

treatment. (Top right) 18F-FLT scans of rep-

resentative H460 tumor–bearing mouse of

control group. (Bottom left) 18F-FDG scansof representative PC3 tumor–bearing mouse

during bevacizumab treatment. (Bottom

right) 18F-FDG scans of representative PC3

tumor–bearing mouse of control group. Ineach panel, upper row contains Cerenkov

luminescence images, and bottom row con-

tains PET images; for each row, left halfcontains prescans at day 23, and right half

contains scans at day 3.

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has high throughput, and, finally, it has widely availablelong-established optical imaging instruments. Since its in-ception, CLI has been quickly studied for a variety of appli-cations including traditional molecular imaging applicationssuch as in vivo tumor imaging (2,3), reporter gene imaging(12), and source-depth measurement/tomography (26,27).More novel applications include use of Cerenkov photons toexcite fluorescent materials such as quantum dots (25,28),high-resolution imaging (29), PET/MRI/OI triple-modalityimaging probe development (13), and many others. Never-theless, there are still important potential applications ofCLI that have not been explored, and preclinical cancertherapy monitoring is among the most promising possibil-ities of CLI.

18F-FLT and 18F-FDG are 2 well-known PET probes thathave been extensively used for both preclinical and clinicalapplications. One prominent example is cancer therapymonitoring. We hypothesized that CLI could be an impor-tant bridge linking clinically approved radioactive probes toOI modalities for monitoring therapeutic effects of antican-cer agents. Yet the effectiveness of CLI for therapy monitor-ing lies essentially with its quantification capability insubcutaneous tumor models; even more important is whethera good correlation exists between CLI and the gold standardnuclear imaging counterparts. Our results showed that atleast for the b1-emitter 18F-based probes such as 18F-FLT

and 18F-FDG, there is an excellent correlation between thequantifications of the 2 modalities, regardless of the xeno-grafts studied or of the treatment. It is also foreseeable thatother radionuclides that have been shown to emit significantCR photons can be used to monitor cancer therapies becausethe fundamental mechanism of CLI remains the same re-gardless of the radionuclides.

In the previous sections, we outlined the advantages ofusing CLI to monitor therapeutic effects. Intrinsic featuressuch as low cost, high sensitivity, short acquisition time, highthroughput, and a relatively flat learning curve can benefitthe labors of researchers and clinicians alike. Especially intime-consuming, large-scale projects such as drug screening,the efficiency that OI brings can be paramount. There is alsoan abundance of radioactive probes that are currently ap-proved by the Food and Drug Administration and availablefor therapy monitoring. By way of contrast, there are onlya limited number of approved OI agents. One can foreseethat not only b1-emitters but also clinically importantb2-emitters such as 32P, 90Y, and 131I can be imaged viaCLI, either for therapy monitoring or for several other po-tential applications. Yet another advantage of CLI lies in itsversatility when compared with traditional imaging modali-ties such as bioluminescence imaging. CLI not only allowsfor concurrent PET but also eliminates the need for reporterdelivery, which is essential in bioluminescence imaging. This

FIGURE 4. Quantitative analysis of Cerenkov luminescence and PET images and their correlation calculated through fitting by linear

regression. P , 0.0001 for all 4 linear regressions. (A) H460 xenografts with bevacizumab treatment. (B) H460 xenografts of control group.

(C) PC3 xenografts with bevacizumab treatment. (D) PC3 xenografts of control group.

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difference becomes particularly important in potential clini-cal applications for which reporter gene imaging can becumbersome whereas CLI simply requires an injection ofradioactive probes. In general, however, bioluminescenceimaging is more sensitive than CLI (2).Although CLI therapy monitoring enjoys many advan-

tages over traditional nuclear imaging modalities, the re-quirement of OI also poses some inevitable limitations thatare intrinsic to optical imaging as well. Optical signalattenuation and scattering in living animals along with theparticular spectrum of CR always result in reduced signalintensity—the deeper the source of the signal, the lower thesensitivity and the poorer the quantification of CLI. Yetin typical preclinical drug-screening applications, one canlargely avoid these shortcomings using subcutaneous xeno-grafts in small animals, much like the models used in thisstudy. In clinical situations, superficial disease processessuch as dermatologic neoplasms and inflammations can alsobe imaged by CLI during treatment if deemed necessary byclinicians. More importantly, deep disease processes acces-sible by techniques based on charge-coupled device or fiberoptic cameras, such as endoscopies and colonoscopies, canbe potentially monitored with high sensitivity and quantifi-cation capability by CLI as well. Furthermore, intraoperativeCLI has also been envisioned and is currently being activelyexplored. Holland et al. recently published an interestingpiece of research demonstrating image-guided intraoperativeresection of tumors from murine models (30). It is thus fore-seeable that in the near future intraoperative CLI can benefitsurgeons by providing real-time anatomic and functional in-formation about tumors and metastases.

CONCLUSION

CLI and PET exhibit excellent correlations acrossdifferent tumor xenografts and radiotracers in both treatedand untreated mice by bevacizumab. To the best of ourknowledge, this is the first study to demonstrate the use ofCLI for monitoring cancer treatment. The findings warrantfurther exploration and optimization of CLI as a lessexpensive, easier-to-use, and high-throughput alternativeto PET in preclinical therapeutic monitoring studies anddrug-screening processes.

DISCLOSURE STATEMENT

The costs of publication of this article were defrayed inpart by the payment of page charges. Therefore, and solelyto indicate this fact, this article is hereby marked “adver-tisement” in accordance with 18 USC section 1734.

ACKNOWLEDGMENTS

We acknowledge support from the National CancerInstitute (NCI) R01 CA128908 and Stanford MedicalScholar Research Fellowship. No other potential conflictof interest relevant to this article was reported.

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Doi: 10.2967/jnumed.111.094623Published online: January 12, 2012.

2012;53:312-317.J Nucl Med.   Yingding Xu, Edwin Chang, Hongguang Liu, Han Jiang, Sanjiv Sam Gambhir and Zhen Cheng  Luminescence ImagingProof-of-Concept Study of Monitoring Cancer Drug Therapy with Cerenkov

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